The optimal method of administering antiviral agents is by oral ingestion or other enteral means. With enteral dosing it is difficult, yet most desirable, to achieve maximum systemic absorption of the agent. The term oral bioavailability, for example, refers to the extent of systemic absorption of the agent when administered orally. It is well known that plasma drug concentrations, pharmacoiogic activity, and toxicity are controlled best when oral bioavailability is maximized. Poor oral bioavailability is usually associated with greater inter-subject and intra-subject variability in plasma drug concentrations, inconsistent pharmacologic activity, and unpredictable toxicity. In addition, since unabsorbed drug is essentially wasted, maximization of oral bioavailability is a means of minimizing the drug dosage requirements, which minimizes cost.
Some of the cyclic urea type antiviral agents of the present invention have exhibited poor oral bioavailability when administered in conventional formulations at relatively low doses. Others have exhibited adequate oral bioavailability at low doses, but had poor oral bioavailability at higher doses using conventional formulations. The administration of higher doses of these agents, and the attainment of drug concentrations in plasma, tissues, or other body fluids that are at or above the viral inhibitory concentrations of these agents is desirable for greatest antiviral efficacy.
Where oral bioavailability of compounds (especially compounds having low aqueous solubility) is a problem, a typical approach is to administer the drug dissolved in a non-aqueous, water miscible solvent, such as a polyethylene glycol (particularly those with low molecular weights), propylene glycol, and/or ethanol. Such solution formulations were useful for attaining suitable oral bioavailability at low doses of the antiviral agents of the present invention. However, as doses were increased in an attempt to produce greater drug concentrations in plasma, bioavailability was reduced, and plasma concentrations did not increase with increasing doses. In short, non-aqueous, water-miscible solution formulations containing polyethylene glycol, propylene glycol, ethanol, or combinations of these ingredients, were not useful for achieving good oral bioavailability with high doses of the subject cyclic urea antiviral agents.
Another generally useful approach to improve oral bioavailability that is known to those skilled in the art of drug formulation, is to disperse the drug in a solid mixture comprised of water-soluble solids such as polyethylene glycol or polyvinylpyrrolidone. These dispersions can be prepared by dissolving or co-melting the drug in the melted water-soluble carrier at high temperature, referred to as the fusion method. Dispersions can also be prepared by dissolving the drug and the water-soluble solid in a suitable solvent for all ingredients, and then evaporating the solvent. This is referred to as the solvent evaporation method. Chiou and Riegelman, J. Pharm. Sci., 60:1376-1380 (1971) have shown that oral bioavailability of griseofulvin was increased in humans when administered in a solid dispersion formulation, compared to a conventional solid formulation containing micronized griseofulvin. The solid dispersions of this example consisted of griseofulvin and polyethylene glycol 6000 in a 1:9 (w:w) ratio, and they were prepared by either the fusion or solvent evaporation methods. In contrast, in the case of antiviral agents of the present invention, low oral bioavailability was observed using solid dispersion formulations containing polyethylene glycol 3350 or a combination of polyethylene glycol 3350 and polyvinylpyrrolidone.
Other compositions have been reported to improve the oral bioavailability of certain specific drugs. Ishimura et al., in European Patent Application 0 371 471 A1 (Jun. 6, 1990), for example, disclosed compositions for improved drug absorption of the drug (.+-.)-2-carbamoyloxymethyl-4-(2,3-dichlorophenyl-6-methyl-1,4-dihydropyri dine-3,5-dicarboxylic acid 3-isopropyl ester 5-methyl ester (or its optical isomer), comprising solid dispersions of the drug in a water-soluble or enteric-soluble polymer, and a non-ionic surfactant. The preferred non-ionic surfactants claimed in EP 371,471 were glycerine fatty acid ester, glycerol monostearate, acetylated glycerine stearate, acetylated glycerine fatty acid ester, sorbitan fatty acid ester, sorbitan monolaurate, sorbitan sesquioleate, sorbitan monooleate, sorbitan trioleate, polyoxyl 40 stearate, or sucrose fatty acid ester.
Adjei et al., in European Patent Application 370 A1 (Feb. 8, 1988), disclose compositions useful for improving the oral absorption of erythromycin. These compositions contained a triglyceride oil and N-methyl pyrrolidone. Similar vehicle formulations were also claimed in PCT application WO 90/08537 (Aug. 9, 1990) to be useful for improving the oral absorption of other pharmaceutical agents.
Behl et al., in U.S. Pat. No. 4,525,339 (Jun. 25, 1985), disclose compositions useful for improving oral activity of beta lactam antibiotics. These compositions contain mono-, di-, and triglycerides of C.sub.2 -C.sub.12 chain length fatty acids. The compositions are enteric coated.
Saeki et al., in U.S. Pat. No. 4,827,062 (May 2, 1989), describe a composition for improving the oral absorption of the compound ubidecarenone comprising a glycerol monounsaturated fatty acid ester, a propylene glycol monounsaturated fatty acid ester, or a mixture thereof, and a liquid oil. The preferred fatty acid of the glycerol and propylene glycol esters was oleic acid. However, when tested in combination with cyclic urea compounds of the present invention, vehicles employing glycerol monooleate, oleic acid and propylene glycol fatty acid esters were found to be unsuitable for improving the oral absorption of these compounds.
Cavanak and Sucker, in Prog. Allergy 38: 65-72 (1986), describe the development of cyclosporin formulations which afforded good oral absorption. A preferred formulation contained cyclosporin in a mixture of olive oil, ethanol, and ethoxylated persic oil. The ethoxylated persic oil used was a commercial brand referred to as Labrafil.TM. M 1944 CS, which is known to contain glycerides and polyethylene glycol esters.
As the foregoing indicates, a number of examples exist where particular vehicles have been found useful in increasing the bioavailability of certain specific drugs. However, it is difficult to extrapolate any such findings from one type or class of drug to another. For example, although it is known generally in the art that polyethylene glycol, propylene glycol and ethanol may increase oral bioavailability of compounds, such formulations were not useful for achieving good oral bioavailability with high doses of the subject cyclic urea antiviral agents. Similarly, notwithstanding the apparent success in Saeki et al, U.S. Pat. No. 4,827,062 with vehicles for the drug ubidecarenone comprised of glycerol monounsaturated fatty acid esters and/or propylene glycol monounsaturated fatty acid esters, vehicles employing glycerol monooleate, oleic acid and propylene glycol fatty acid esters were found to be unsuitable for improving oral absorption of the cyclic urea compounds of the present invention. Moreover, solid dispersion formulations containing polyethylene glycol 3350 or a combination of polyethylene glycol 3350 and polyvinylpyrrolidone were tested and found to be unsuitable for improving the oral bioavailability of cyclic urea compounds of the present invention, despite the teachings in the art, including the teachings in Chiou and Riegelman, J. Pharm. Sci., 60:1376-1380 (1971), where griseofulvin bioavailability was increased with similar solid dispersion formulations.
In the present invention, pharmaceutical compositions have been discovered which provide good bioavailability for the cyclic urea antiviral compounds disclosed herein. The subject formulations allow good systemic absorption of the antiviral agents when administered orally or by other enteral means, not only at low doses, but also at high dosage levels. This, in turn, permits better control of plasma drug concentrations, pharmacologic activity and drug toxicity, and minimizes cost by reducing drug loss from poor systemic absorption. These and/or other advantages of the present invention are further described below.